Synthesis of o-diorganylphosphino-substituted benzoic acids and their derivatives

Article abstract of DOI:10.1007/s11176-005-0368-x

o-Substituted dialkyl- and alkylphenylphosphinobenzoic acids, as well as their esters, nitriles, and amides, including those containing three different substituents on the phosphorus atom, were prepared for the first time by two different synthetic procedures. The most general procedure involves metal-halogen exchange in bromo- and iodoarenes, followed by phosphorylation of the resulting lithium derivatives. 2005 Pleiades Publishing, Inc.

Full text of DOI:10.1007/s11176-005-0368-x

Russian Journal of General Chemistry, Vol. 75, No. 7, 2005, pp. 1060 1068. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 7, 2005,
pp. 1122 1131.
Original Russian Text Copyright
2005 by Veits, Neganova, Vinogradova.
Synthesis of o-Diorganylphosphino-substituted Benzoic Acids
and Their Derivatives
Yu. A. Veits, E. G. Neganova, and O. S. Vinogradova
Lomonosov Moscow State University, Moscow, Russia
Received March 16, 2004
Abstract o-Substituted dialkyl- and alkylphenylphosphinobenzoic acids, as well as their esters, nitriles,
and amides, including those containing three different substituents on the phosphorus atom, were prepared for
the first time by two different synthetic procedures. The most general procedure involves metal halogen ex-
change in bromo- and iodoarenes, followed by phosphorylation of the resulting lithium derivatives.
Reactions catalyzed by metal complexes have recently successfully extended to secondary functionalyzed
taken on great significance [1, 2]. In this connection
the search for new organophosphorus ligands, es-
pecially those containing hydrophilic substituents that
render complexes on their basis water-soluble, has
become urgent. Water-soluble phosphine ligands,
including P- and C-chiral, are attracting growing re-
searcher’s attention [3 6].
alkylarylphosphines [8] and vinylphosphines [9].
Later on the same cross-coupling reaction was per-
formed with phenyl- and diphenylphosphines (or their
complexes with BH3) instead of silylphosphines
[10 14], which allowed iodine-substituted arylcarb-
oxylic and arylsulfonic acids and phenols to be
included in the range of electrophilic reagents [15 17].
Just recently the first short communication concerning
the synthesis of tertiary diphenylarylphosphines with
the acetyl and methoxycarbonyl groups in the aryl
substituent by the cross coupling of diphenylphos-
phine with iodoarenes, catalyzed by copper iodide,
appeared [18].
The aim of this work was to develop methods for
synthesis of phosphines of the general formula 2-
(R1R1P)-C6H4Y
I
(R
=
s- and t-Alk, Ar;
Y = COOH, COOR, CN, CONR2), that is derivatives
of o-phosphino-substituted benzoic acids, potentially
chiral and water-soluble.
Historically, the first method of synthesis of ter-
tiary aromatic phosphines containing functional
In [19], we found that the conditions of the syn-
thesis by the Stille reaction of tertiary phosphines I
groups sensitive to organometalllic reagents and, there- with Y = COOR, even with one secondary or tertiary
fore, excluding the application of organolithium and
organomagnesium reagents, is the Stille reaction [7].
It involves cross coupling of (trimethylsilyl)diphenyl-
phosphine with functionally-substituted aryl halides,
catalyzed by Pd(0) complexes. This reaction was
alkyl radical on phosphorus, become, in view of the
steric hindrances, so rigid that the major cross-coupl-
ing products in this case are not phosphines I but
teriary phosphonium salts formed by the side reac-
tions presented in scheme (1).
PR1R2
P+R1R2R3 X
(1)
COOSiMe3
PR1R2
X
Me3SiX, t
t
3 5 mol% Pd(0)
+ R3X
COOSiMe3
R1R2PSiMe3 +
Me3SiCl
COOR3
COOR3
I
R1 = i-Pr, t-Bu; R2 = Ph; R3 = Me, Et; X = Br, I.
These results prompted us to investigate the cross
coupling of dialkyl- or alkylarylphosphines with
bromo- and iodobenzoic acids, as well as their deriva-
tives (esters, amides, nitriles), under the conditions
described in [15, 16]. The greatest interest presented
the synthesis of hardly available o-phosphino-substi-
tuted benzoic acids that, like our chosen secondary
phosphines, were not studied in the cited works.
1070-3632/05/7507-1060 2005 Pleiades Publishing, Inc.

SYNTHESIS OF o-DIORGANYLPHOSPHINO-SUBSTITUTED BENZOIC ACIDS
1061
First of all we have studied as a model the cross
coupling of diphenylphosphine with o-iodobenzoic
acid and found that this reaction, unlike the previously
reported reaction of m-bromobenzoic acid, yielding
corresponding phosphine I [17], gave no phosphine Ia.
that phosphines Ia and Ib are most probably not
primary products of reaction (2), and the whole set of
compounds that appear in the downfield region of the
31P NMR spectra results from intricate reactions of
secondary phosphines with the carboxy group of o-
iodobenzoic acid. Nevertheless, it should be men-
tioned that the successful synthesis of phosphine Ic
by reaction (3) is the first example of cross coupling
of dialkylphosphines with halobenzoic acids, that
opens the way to dialkylphosphino-substituted ben-
zoic acids. The enhanced steric hindrances on repla-
cement of diisipropylphospihe by tert-butyl(isopropyl)-
phosphine revealed themselves in that cross coupling
with m-iodobenzoic acid failed to occur even on heat-
ing at 100 C for 20 h. At the same time, the 31P NMR
spectrum of the reaction mixture contained no new
signals but that of the starting phosphine. These data
provide further evidence to show that cross coupling
is sensitive to the steric structure of both reagents.
PR2
I
3 5 mol% Pd(0)
2Et3N, 100 C
(2)
R2PH +
COOH
COOH
Ia, Ib
I, R = Ph (a), i-Pr (b).
As judged from the 31P NMR spectra, after 12 h of
heating of the reaction mixture in a sealed ampule
diphenylphosphine is consumed completely, but,
instead of phosphine Ia, a mixture of phosphino-
substituted compounds is formed. The mixture con-
tains one major product ( 14.4 ppm) and four com-
P
pounds ( 27 32 ppm) that, by tabulated
values
P
P
[20], are suggested to involve a Ph2P(O) group. No
of these signals is attributable to phosphine Ia, since
With derivatives of o-bromo- and o-iodobenzoic
acids, the situation in the cross-coupling reactions
was each time different but predictable and controlled
primarily by the steric properties of the phosphine and
the electrophilicity of the o-halobenzoic acid deriva-
tive [reaction (4)].
the
values of triarylphosphines (for Ph3P,
P
P
6 ppm) substituted in the o-position span the range
5 to 20 ppm [17]. Actually, phosphine Ia prepared
by another procedure had
4.05 ppm. Probably,
under the conditions of reactPion (2), oxidation of tri-
valent phosphorus compounds takes place, and the
source of oxygen is the carboxy group that is oxidized
in fairly rigid conditions. Analogous processes,
especially facile with aldehydes and ketones, are well
known in the chemistry of organophosphorus com-
pounds [21].
PPr2-i
X
Y
Pd(0)
i-Pr2PH +
(4)
2Et3N, 100 C
Y
Id Ig
I, Y = CONMe2 (d), COOCH3 (e), COOSiMe3 (f), CN
(g); X = = I, Br.
Reaction (2) with diisopropylphosphine, a more
nucleophilic but stronger sterically congested reagent,
occurs much slower: After 25 h at 100 C more than
one third of the phosphine remains unreacted. In other
aspects, the reaction pattern is similar to that de-
scribed above for diphenylphosphine, viz. the reaction
gives no phosphine Ib and provides a mixture of
With the least electrophilic N,N-dimethyl-o-iodo-
benzamide, reaction (4) did not take place even for
20 h at 100 C. Even after 50 h at that temperature, in
the 31P NMR spectrum of the reaction mixture we
could detect ca. 15% of phosphine Id (
0.28 ppm).
P
The major reaction products were tetraisopropyldi-
phosphine (50%, 13 ppm) [22] and compounds
with
56 and 6P2 ppm, that is those containing
a compound with
27 ppm and four compounds
with
54 57 ppmP, that contain, according to ta-
bulatedP data [20], an i-Pr2P(O) fragment.
i-Pr2P(O) and i-Pr2P(O)O groups (the analog of phos-
phine Id with Y = CONEt2 we prepared in high yield
by another procedure). The more electrophilic o-halo-
benzoic acid esters slightly faster react with diisopro-
pylphosphine. Hence, after 12 h at 100 C, ca. 20% of
phosphine Ie ( 3.5 ppm) and ca. 10% of phosphine
If ( 2.9 ppm)P were detected. Note that in the first
case Pwe used methyl o-bromobenzoate and in the
second case, trimethylsilyl o-iodobenzoate. After
30 h at 100 C, the mixture contained ca. 40% of
phosphine Ie, but longer heating at 100 C (higher
temperatures are still less favorable) caused decom-
position of phosphine Ie and formation of several
P
At the same time, the reaction of diisopropylphos-
phine with m-iodobenzoic acid is complete within 10
12 h at 100 C to form phosphine Ic ( 11.5 ppm) in
P
a nearly quantitative yield.
PPr2-i
I
Pd(0)
(3)
COOH
i-Pr2PH +
2Et3N, 100 C
COOH
Ic
The thermal stability data for phosphine Ic suggest
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 7 2005

1062
VEITS et al.
compounds with
40 60 ppm. These findings
expect that it would require much milder conditions
to occur (phenyllithium fast reacts at reduced tem-
peratures even with di-tert-butylchlorophosphine. The
main complication was that, even though the syn-
theses of o-lithiated benzoic acid both by direct metala-
tion [23 25] and by halogen lithium exchange [26
30], as well as the syntheses of o-lithiated benzoic
acid derivatives by the first [31 33] or second [26 28,
34 37] methods are well-documented, comparative
and systematic analysis of the results obtained by
different methods and with different derivatives was
lacking from the literature. Moreover, all subsequent
reactions of o-lithiated derivatives were performed
with electrophiles other than P(III) chlorides (mainly
D2O, alkyl and acyl halides, and carbonyl compounds).
suggest that the o-alPkoxycarbonyl group, like o-carb-
oxyl, effects oxidation of P(III), though to a lesser
extent. As a result, phosphines Ie and If containing
an ester group can be synthesized in 30 40% yields
by reaction (4).
Finally, o-bromobenzonitile reacts with diisopro-
pylphosphine faster than o-halobenzoic acid esters.
Therewith, the synthesis of phosphine Ig is not com-
plicated by side processes (which is most probably
associated with the absence of the oxygen atom in the
C N group), and the content of the target product in
the reaction mixture after 45-h heating at 100 C was
82%. Phosphine Ig is thermally stable and was iso-
lated in high yield by vacuum distillation.
Analysis of published data permitted us to con-
clude that the most suitable starting compounds for
preparing o-lithiated derivatives of benzoic acid both
by direct metalation and by exchange reactions are
amides and nitriles, whereas free acids and their esters
(except for the strongly shielded tert-butyl esters) are
less suitable. As to the synthetic procedures, then,
even though they both have certain disadvantages,
halogen metal exchange reactions are more facile
(15 45 min at 100 C) and provide higher yields of
aryllithium compounds (70 90%). Direct metalation
of the cheaper and available benzoic acid and its esters
proceeds much slower (up to 1.5 2 h at 100 C) with
50 65% converion. Therewith, even at such a low
temperature o-lithiated n-alkyl esters noticeably
decompose.
Sterically more hindered phosphines, such as tert-
butyl(isopropyl)- and tert-butyl(phenyl)phosphines,
fail to react even with o-bromobenzonitrile. Hence,
cross coupling with the first phosphine did not begin
even after heating at 100 C for 25 h. In the 31P NMR
spectrum, the signal of the starting phosphine
remained unchanged. With the second phosphine,
several unidentified organophosphorus compouns
were formed, but the target product, that is phosphine
I, was absent.
Analysis of the resulting data on the cross coupling
of secondary phosphines with o-halo-substituted
benzoic acids and their derivatives allows us to
conclude that reactions (2) and (4) are of low prepa-
rative significance for a broad range of phosphines
sterically more hindered than diisopropylphosphine.
This result prompted us to focus on another synthetic
route to 2-phosphino-substituted benzoic acids and
their derivatives, based on the reaction of o-lithiated
derivatives of the latter with chlorophosphines.
In view of the above findings, we have chosen halo-
gen lithium exchange as the most universal and
experimentally convenient method for preparing not
only o-, but also m- and p-lithiated benzoic acid
derivatives (as shown in [29, 30], m- and p-lithiated
salts of benzoic acid prepared in 60 85% yield by this
reaction are thermally stable at 78 C for 1.5 2 h).
1) 1 or 2 BuLi,
90 to 100 C;
X
Y
PR1R2
(5)
Y
2) R1R2PCl
i-Pr2PH +
Before investigation of the synthesis of phosphine
I by reaction (5), we tried to reproduce the halogen
lithium exchange reaction of o-, m, and p-iodobenzoic
acids under the action of butyllithium and subsequent
reaction of the resulting aryllithium salts with chloro-
trimethylsilane [reaction (6)], presented in [29, 30].
X = H, Br; Y = COOH, COOR, CONR2, CN.
By changing the polarity of the reagents in reac-
tion (5) as compared to the previous cases we might
SiMe3
X
Bu
1) 2BuLi, 100 C,
2) 2.2Me3SiCl
+
(6)
COOSiMe3
COOH
COOSiMe3
IIIb, IIIc
X = Br (o-, m-), I (p-); IIa, IIb, o- (a), m- (b); III, m- (b), p- (c).
IIa, IIb
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 7 2005

SYNTHESIS OF o-DIORGANYLPHOSPHINO-SUBSTITUTED BENZOIC ACIDS
1063
Table 1. Constants, yields, and elemental analyses of phosphines R1R2PC6H4Y Ia Ic and If Il
Yield, %
Methoda (by 31P
data)
Found, %
H
Calculated, %
bp,
(p, mm Hg)
C
R1 R2
Y
Formula
C
N
C
H
N
Ia Ph Ph 2-COOH
Ib i-Pr i-Pr 2-COOH
B
B
A
B
B
A
B
B
B
B
B
60 (87)
159
74.05 4.61
C19H15O2P 74.50 4.94
C13H19O2P 65.53 8.04
C13H19O2P 65.53 8.04
C16H27O2PSi 61.90 8.77
50 (70) 107 112 (1) 65.15 7.92
70 (90) 120 124 (1) 65.08 7.85
70 (86) 86 88 (1) 61.56 8.61
58 (80) 90 92 (1) 79.78 7.95 5.90 C13H18NP
70 (90) 90 92 (1)
58 (90)
30
28
Ic
If
i-Pr i-Pr 3-COOH
i-Pr i-Pr 2-COOSiMe3
Ig i-Pr i-Pr 2-CN
Ig i-Pr i-Pr 2-CN
Ih t-Bu Ph 2-COOH
71.21 8.27 4.77
b
71.05 6.65
74.12 4.68
C17H19O2P 71.32 6.79
C19H15O2P 74.50 4.94
C16H27O2PSi 61.90 8.77
Ii
Ij
Ph Ph 3-COOH
i-Pr i-Pr 3-COOSiMe3
128
90 95 (1) 61.62 8.55
Ik i-Pr i-Pr 2-C(O)NEt2
Il i-Pr t-Bu 2-C(O)NEt2
79 (97) 132 135 (1) 69.05 9.15 4.35 C17H28NOP 69.60 9.62 4.77
72 (95) 138 140 (1) 69.98 9.62 4.32 C18H30NOP 70.33 9.84 4.56
a
(A) Cross coupling of secondary phosphines with aryl halides and (B) reaction of o- or m-lithiated benzoic acids or their derivatives
b
with chlorodiorganylphosphines.
Oil.
The results of reaction (6) occurred to be quite
1) 2BuLi, 100 C;
unexpected. With o-bromobenzoic acid, we obtained
nothing more than the expected product, trimethylsilyl
o-(trimethylsilyl)benzoate (IIa). With m-bromo-
benzoic acid, a mixture of silyl esters of m-(trimethyl-
silyl)benzoic IIb and m-butylbenzoic acids IIIb was
obtained. Ester IIIb was the major product (>80%)
when we used the conditions described in [29, 30] to
prepare the m-lithiated salt (1.5 h at 95 C before
addition of the electrophilic agent). Even if the
lithium salt had been kept for a short time (5 10 min
at 100 C) before chlorotrimethylsilane was added,
2) R1R2PCl, 90 20 C;
3) H3O+, pH 3 4
PR1R2
COOH
Br
(7)
COOH
Ia, Ib, Ih
I, R1 = R2 = Ph (a); R1 = R2 = i-Pr (b); R1 = t-Bu, R2 =
Ph (h).
to a solution of o-bromobenzoic acid in ether (with
THF, the yield of compounds I is not better) is 30
40 min. The optimal amount of diorganylphosphine is
0.7 0.8 mol/mol benzoic acid, because the yields of
the aryllithium salts do not exceed 80%. The spectral
yield of phosphines I is 85 90%, and the isolable
yield, 60 70% (Table 1). With equimolar amounts of
chlorophosphines, by-products appear in the reaction
mixtures, the most abundant of them being R1R2
1
the fraction of expected product IIb, according to H
NMR, was no more than 35%, and ester IIIb still
remained the preferred product. In the case of p-iodo-
benzoic acid, the substitution product of p-lithiated
lithium benzoate with chlorotrimethylsilane, ester IIc,
was not detected even spectrally. Instead, trimethyl-
silyl p-butylbenzoate (IIIc) formed, implying that the
p-aryllithium salt completely reacts with butyl iodide
even at 100 C for 10 20 min (i.e. the time of addi-
tion of butyllithium). These results we could re-
peatedly reproduce. They disagree with the results in
[29, 30] and suggest that with m- and p-bromo(iodo)-
benzoic acids and their derivatives one should use
bases sterically more hindered than butyllithium.
POBu,
R1R2P(O)Bu,
and
compounds with
R1R2P(O)O fragments. The presence of by-products
makes phosphines I much more difficult to isolate
pure.
Phosphino-substituted benzoic acids Ia, Ib, and Ih
should be isolated with certain precautions: After the
reaction mixtures had been decomposed with water,
and the organic layer separated, the aqueous layer
containing lithium salts of acids Ia, Ib, and Ih should
be treated with 5% HCl very carefully, so that the pH
of the solution is no higher than 3 4 units, because
in a more acidic medium the products are protonated
by the phosphorus atom, the easiest protonated being
Since o-diorganylphosphino-substituted benzoic
acids Ia and Ib could not be synthesized by cross-
coupling reaction (2), we synthesized them by a
scheme analogous to scheme (5).
The time of handling of the reaction mixture after
a solution of butyllithium in hexane has been added
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 7 2005

1064
VEITS et al.
5 ppm). With excess alkali, however, facile
the most basic dialkylphosphino-substituted derivative
Ib. Treatment phosphonium salt IV ( 34 ppm) with
equimolar amount of aqueousethanoliPc NaOH gives
rise to sodium salt V
(
P
cleavage of the phosphorus aryl bond takes place to
1
form diisopropylphosphinous acid ( 54 ppm, JPH
P
430 Hz [20]) [scheme (8)].
P+(H)Pr2-i Cl
PPr2-i
HCl
2NaOH
EtOH
NaOH
H2O
(8)
Ib
i-Pr2P(O)H + PhCOONa
COOH
COONa
IV
V
Replacement of hydrochloric acid with a concen-
trated solution of ammonium chloride results in
slower neutralization and requires longer contact with
lithium salt of acid Ib and does not improve the yield
of acid Ib significantly (by 31P NMR, ca. 60%). The
main difficultly is isolation of phosphino-substituted
acids Ia, Ib, and Ih is associated that the ester and
and diorganylphosphino groups in them are very close
to each other in basicity (pKa values of the conjugate
acids differ by 1 2), and, consequently, suitable acids
for neutralization of lithium salts of theses acids
should not protonate the P(III) atom.
phosphines did not exceed 30%, which agrees with
the yield of silyl ester of m-trimethylsilylbenzoic acid
IIb and is explained by the same reasons.
The halogen lithium exchange for preparing phos-
phines I was studied with nitriles and N,N-diethyl-
amides of o-bromobenzoic acid [reaction (10)].
1) 2BuLi, 100 C;
PR1R2
2) R1R2PCl
Br
Y
(10)
Y
Ig, Ik, Il
Isolation of compounds Ia and Ih with less basic
R1R2P fragments is not associated with the above
difficulties. Nevertheless, to simplify this process, we
developed a procedure that excludes aquoeus-acidic
treatment of the reaction mixtures and involving
treatment of lithium salts of compounds I with excess
chlorotrimethylsilane followed by vacuum distillation
of trimethylsilyl esters of acids I. The spectral yields
of the silyl esters reach 85 90% (phosphine If was
isolated in 70% yield, whereas its yield by cross
coupling (4) was no higher than 30%). If necessary,
silyl esters of acids I can be easily hydrolyzed to give
the corresponding acids under mild conditions [8].
I, R1 = R2 = i-Pr, Y = CN (g); R1 = R2 = i-Pr, Y =
CONEt2 (k); R1 = i-Pr, R2 = t-Bu, Y = CONEt2 (l).
Especially good results in reaction (10) were obtai-
ned with phosphines Ik and Il (by 31P NMR, 95
98%) that could not be prepared by cross coupling (4).
To conclude, the cross-coupling reactions of di-
alkyl(trimethylsilyl)phosphines and secondary phos-
phines with o-halosubstituted benzoic acids and their
derivatives failed to provide sterically congested
o-dialkylphosphino-substituted compounds (nitrile Ig,
R1 = R2 = i-Pr, was the only exception). At the same
time, in the reactions of o-lithiated benzoic acid and
its derivatives with diorganylchlorophosphines steric
hindrances did not play the decisive role, which al-
lowed us to prepare by this procedure a series of
previously unavailable phosphines I. Their yields,
constants, and spectral characteristics are listed
Tables 1 and 2.
On attempted synthesis of m-diorganylphosphino-
substituted benzoic acid Ii or trimethylsilyl ester Ij
from m-iodobenzoic acid by reaction (7) the yields of
1) 2BuLi, 100 C;
2) Ph2PCl;
PPh2
3) H3O+
I
EXPERIMENTAL
The H and 31P NMR spectra were obtained on a
COOH
(9)
1
Ii
1) 2BuLi, 100 C;
2) 2i-Ph2PCl;
3) Me3SiCl
Varian VXR-400 spectrometer against internal TMS
COOH
PPr2-i
(1H) and external 85% phosphoric acid (31P).
All manipulations with phosphines were carried
out under dry argon. The solvents were purified by
standard procedures and degassed in a vacuum under
cooling and them purged with argon (2 3 times).
COOSiMe3
Ij
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 7 2005

SYNTHESIS OF o-DIORGANYLPHOSPHINO-SUBSTITUTED BENZOIC ACIDS
Table 2. 1H and 31P NMR spectra of phosphines I
1065
31P NMR spectrum
(CDCl3), P, ppm
1H NMR spectrum (CDCl3), , ppm (J, Hz)
Ia 6.9 8.2 (m)
Ib 0.93 d.d (6H, 8.0), 1.25 d.d (6H, 8.0), 1.79 m (1H), 2.17 m (1H), 7.32 7.9 m (4H)
4.05
7.1
Ic
0.99 d.d (6H, 8.0), 1.16 d.d (6H, 8.0), 2.15 m (1H), 2.52 m (1H), 7.51 t (1H, 7.6), 7.76 t (1H,
7.6), 8.15 d (1H, 7.6), 8.27 s (1H), 10.7 s (1H)
11.5
Ida
Iea
If
0.28
3.5
3.5
0.34 s (9H), 0.9 d.d (6H, 7.0), 1.05 d.d (6H, 7.0), 1.6 m (1H), 2.05 septet (1H, 7.0), 7.29 t
(1H, 6.6), 7.35 t (1H, 6.0), 7.47 d (1H, 7.4), 7.71 d (1H, 7.4)
Ig 0.93 d.d (6H, 8.0), 1.16 d.d (6H, 8.0), 2.23 m (2H, 7.0), 7.45 m (1H), 7.58 br.d (2H, 4.0),
5.91
7.72 m (1H)
Ih 1.43 d (9H, 20), 7.0 8.3 m (9H)
13
Ii
Ij
7.3 8.1 m
5.6
10.8
0.91
0.41 s (9H), 0.93 d.d (6H, 8.0), 1.1 d.d (6H, 8.0), 1.7 m (1H), 2.14 m (1H), 7.4 8.2 m (4H)
Ik 0.85 1.2 m (12H), 1.28 m (6H), 1.97 m (1H), 2.27 m (1H), 3.1 m (2H), 3.43 m (1H), 3.7 m
(1H), 7.21 m (1H), 7.33 m (2H), 7.51 m (1H)
Il
0.84 d.d (3H, 7.0), 1.06 d (9H, 12.0), 1.0 1.3 m (9H), 2.37 septet (1H, 7.0), 3.06 m (2H),
3.45 m (1H), 7.22 m (1H), 7.35 m (2H), 7.55 m (1H)
9.26
a
31
Compounds Id and If were not isolated pure and characterized by the P NMR spectrum only.
Synthesis of phosphines Ic Ie and Ig by
volatile products were removed in a vacuum, and the
residue was distilled to give 0.5 g of phosphine Ig.
cross coupling of diisopropylphosphine with 3-iodo-
benzoic acid and 2-bromobenzoic acid derivatives
(method A). Diisopropyl(3-carboxyphenyl)phos-
phine (Ic). An evacuated and argon-filled ampule was
charged with 0.7 g of m-iodobenzoic acid, 2 ml of
acetonitrile, 0.57 g of triethylamine, 0.4 g of diiso-
propylphosphine, 0.045 g of palladium dichloride, and
0.08 g of 4,5-bis(diphenylphosphino)-9,9-dimethyl-
xanthene, after which it was sealed and thermostated
at 100 C for 10 h with intermittent shaking. By 31P
NMR, this time is enough for complete reaction (spec-
tral yield 75%). The ampule was unsealed, volatile
products were removed in a vacuum, and the residue
was dissolved in 10 ml of benzene and washed with
1 ml of water. The solvent was then removed in a
vacuum, and the residue was distilled to give 0.4 g of
phosphine Ic as a very viscous oil that quickly soli-
dified at 20 C.
Synthesis of phosphines Ia, Ib, If, and Ig Il by
eaction of o- and m-lithiated benzoic acids or
their derivatives with diorganylchlorophosphines
(method B). (2-Carboxyphenyl)diphenylphosphine
(Ia). A two-necked flask equipped with a dropping
funnel and a reflux condenser was evacuated, filled
with argon, charged with a solution of 1 g of o-bromo-
benzoic acid in 20 ml of diethyl ether, and cooled to
95 C. After that 4.75 ml of a 2.1 N solution of butyl-
lithium in hexane was added dropwise over the course
of 40 min. The reaction mixture was stirred for an
additional 30 min at 95 C, and then 0.66 g of di-
phenylchlorophosphine was added dropwise for
20 min. The reaction mixture was stirred for 30 min at
78 C, heated to room temperature, and left overnight,
after which it was treated with 10 ml of argon-purged
water to dissove the precipitate. The aqueous layer
was separated, treated with 2% HCl until pH 3 24
(under these conditions, a colorless precipitate formed)
and extracted with 20 ml of benzene. The organic layer
was separated, and the aqueous layer was treated with
5 ml of 2% HCl and extracted with 10 ml of benzene.
The combined benzene layers were dried over sodium
sulfate, the solvent was removed in a vacuum, and the
residue was crystallized from a 2:1 acetic acid water
mixture to give 0.6 g of phosphine Ia.
(2-Cyanophenyl)diisopropylphosphine (Ig). An
evacuated and argon-filled ampule was charged with
0.36 g of diisopropylphosphine, 0.46 g of o-bromo-
benzonitrile, 0.44 ml of triethylamine, 0.5 ml of
benzonitrile, and 177 mg of PdCl2(CH3CN)2. The
ampule was sealed and thermostated at 100 C for 45 h.
By 31P NMR, this time is enough for complete reac-
tion (spectral yield 80%). The ampule was opened,
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1066
VEITS et al.
(2-Carboxyphenyl)diisopropylphosphine (Ib). A
mixture of diisopropyl[2-(trimethylsiloxycarbonyl)-
ture was stirred for an additional 30 min, and 1.5 g of
tert-butyl(chloro)phenylphosphine was added drop-
phenyl]phosphine (If) prepared from 1.2 g of o-bromo- wise with stirring over the course of 30 nim. The
benzoic acid, 8.26 ml of a 1.44 N solution of butyl-
lithium, 0.68 g of chlorodiisopropylphosphine, and
0.97 g of chlorotrimethylsilane was treated with 3 ml
of methanol and refluxed for 1 h. Volatile products
were removed, and the residue was subjected to a
vacuum (1 mm Hg) to obtain phosphine Ib as a
yellow oil partially crystallizing at room temperature.
When distilled in a vacuum (1 mm Hg), phosphine Ib
underwent partial decomposition.
mixture was stirred for 30 min at 78 C, heated to
room temperature, and left overnight. Argon-purged
water, 30 ml, was then added, and the aqueous layer
was separated, treated with 2% HCl to pH 4, and ex-
tracted with ether (2 20 ml). The ethereal fractions
were combined and dried over sodium sulfate. The
solvent was removed in a vacuum, and the residual
oil was washed with petroleum ether and subjected to
a vacuum (1 mm Hg) for 20 min to give 1.25 of
phosphine Ih as a viscous colorless oil.
Diisopropyl[2-(trimethylsiloxycarbonyl)phenyl]-
phosphine (If). A two-necked flask equipped with a
dropping funnel and a reflux condenser with an argon
inlet was evacuated, filled with argon, charged with a
solution of 0.5 g of o-bromobenzoic acid in 10 ml of
diethyl ether, and cooled to 95 C. After that 2.37 ml
of a 2.1 N solution of butyllithium in hexane was
added dropwise with stirring for 25 min. The reaction
mixture was kept at 95 C for 30 min and then a solu-
tion of 0.29 g of diisopropylchlorophosphine in 5 ml
of diethyl ether was added dropwise for 30 min. The
reaction mixture was stirred at 78 C for 30 min,
heated to room temperature, and, after addition of
0.46 ml of chlorotrimethylsilane, was left overnight.
The colorless precipitate was filtered off on a glass
filter, the solvent was removed in a vacuum, and the
residue was distilled to give 0.32 g of phosphine If.
(3-Carboxyphenyl)diphenylphosphine (Ii).
A
two-necked flask equipped with a dropping funnel and
a reflux condenser with an argon inlet was evacuated,
filled with argon, charged with a solution of 1 g of
m-iodobenzoic acid in 20 ml of diethyl ether, and
cooled to 95 C. After that 3.84 ml of a 2.1 N solu-
tion of butyllithium in hexane was added dropwise
over the course of 30 min. The reaction mixture was
stirred at 95 C for 30 min, and 0.53 g of chlorodi-
phenylphosphine was added dropwise with stirring
over the course of 20 min. The mixture was stirred
for 30 min at 78 C, heated to room temperature, and
left overnight. Argon-purged water, 30 ml, was then
added (the precipitate that formed completely dis-
solved), and the aqueous layer was separated, treated
with 2% HCl to pH 4 (a colorless precipitate formed),
and extracted with benzene (2 20 ml). The benzene
fractions were combined and dried over sodium sul-
fate. The solvent was removed in a vacuum, and the
residue crystallized from 2:1 acetic acid water to give
0.33 g of phosphine Ii.
(2-Cyanophenyl)diisopropylphosphine (Ig). A
two-necked flask equipped with a dropping funnel and
a reflux codenser, and an argon inlet was evacuated,
filled with argon, charged with 2.1 ml of o-bromo-
benzonitrile in 40 ml of diethyl ether, and cooled to
95 C. After that 7.23 ml of a 1.44 N solution of
butyllithium in hexane was added over the course of
15 min. The reaction mixture was stirred for an
additional 20 min at 95 C, and 1.26 g of diisopropyl-
phosphine was added over the course of 10 min. The
mixture was stirred for 15 min at 78 C, heated to
room temperature, and left overnight. The colorless
precipitate was filtered off on a glass filter, the solvent
was removed, and the residue was distilled in a
vacuum to give 1.05 g of phosphine Ig as a viscous
oil.
Diisopropyl[3-(trimethylsiloxycarbonyl)phenyl]-
phosphine (Ij). A two-necked flask equipped with a
dropping funnel and a reflux condenser with an argon
inlet was evacuated, filled with argon, charged with a
solution of 1 g of m-iodobenzoic acid in 20 ml of di-
ethyl ether, and cooled to 95 C. After that 3.84 ml
of a 2.1 N solution of butyllithium in hexane were
added dropwise with stirring over the course of
30 min. The reaction nixture was stirred for 30 min at
95 C, and a solution of 0.43 g of diisipropylchloro-
phosphine in 5 ml of diethyl ether was added drop-
wise with stirring over the course of 20 min. The
mixture was stirred for 30 min at 78 C, heated to
room temperature, and, after addition of 0.75 ml of
chlorotrimethylsilane, was left overnight. The color-
less precipitate was filtered off on a glass filter, the
solvent was removed in a vacuum, and the residue
was distilled to give 0.35 g of phosphine Ij.
tert-Butyl(2-carboxyphenyl)phenylphosphine
(Ih). A two-necked flask equipped with a dropping
funnel and a reflux condenser with an argon inlet was
evacuated, filled with argon, charged with a solution
of 2 g of o-bromobenzoic acid in 20 ml of diethyl
ether, and cooled to 95 C. After that 9.48 ml of a
2.1 N solution of butyllithuim in hexane was added
dropwise with stirring for 45 min. The reaction mix-
[2-(Diethylaminocarbonyl)phenyl]diisopropyl-
phosphine (Ik). A two-necked flask equipped with a
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 7 2005

SYNTHESIS OF o-DIORGANYLPHOSPHINO-SUBSTITUTED BENZOIC ACIDS
1067
dropping funnel and a reflux condenser with an argon was distilled to give 1.75 g of ester IIIb, bp 153
1
inlet was evacuated, filled with argon, charged with a
solution of 2 g of N,N-diethyl-o-bromobenzamide in
40 ml of diethyl ether, and cooled to 95 C. After that
5.43 ml of a 1.44 N solution of butyllithium in hexane
were added dropwise with stirring for 20 min. The
reaction mixture was stirred for 40 min, and a solution
of 0.9 g of chlorodiisipropylphosphine in 5 ml of di-
ethyl ether was added dropwise. The mixture was
stirred for 20 min at 78 C, heated to room tempera-
ture, and left overnight. The precipitate was filtered
on a glass filter under argon, the filtrate was washed
with 2 3 ml of argon-purged water, and dried over
sodium sulfate. The solvents were removed in a
vacuum, and the residue was distilled to give 1.35 g
of phosphine Ik as a viscous oil.
155 C (15 mm Hg). H NMR spectrum (CDCl3), ,
ppm (J, Hz): 0.3 s (9H), 0.94 t (3H, JHH 8.0), 1.39 sexet
(2H, JHH 8.0), 1.7 quintet (2H, JHH 8.0), 2.92 t (2H,
JHH 8.0), 7.31 t (1H, JHH 8.0), 7.63 t (1H, JHH 8.0),
7.85 d (1H, JHH 8.0), 8.06 s (1H). Found, %: C 67.02;
H 8.71. C14H22O2Si. Calculated, %: C 67.15; H 8.86.
At a shorter mlation time and keeping the reaction
mixture for 5 10 min at 95 C, a mixture of trime-
thylsilyl m-butylbenzoate (IIIb) and trimethylsilyl m-
(trimethylsilyl)benzoate (IIb) was obtained, spectral
yields 65 and 35%, respectively.
Trimethylsilyl p-butylbenzoate (IIIb). A two-
necked flask equipped with a dropping funnel and a
reflux condenser with an argon inlet was evacuated,
filled with argon, charged with a solution of 0.8 g of
p-iodobenzoic acid in 20 ml of diethyl ether, and
cooled to 95 C. After that 4.88 ml of a 1.44 N solu-
tion of butyllithium in hexane was added dropwise
with stirring for 15 min, and the reaction mixture was
kept at 95 C for 30 min. A solution of 0.9 ml of
chlorotrimethylsilane in 5 ml of diethyl ether was
added dropwise with stirring for 15 min, and the mix-
ture was stirred for 20 min at 78 C, heated to room
temperature, and left overnight. The colorless preci-
pitate was filtered off on a glass filter, the solvents
were removed in a vacuum, and the residue was dis-
tilled to give 0.5 g (60%) of ester IIIc, bp 145 148 C
Phosphine Il was obtained analogously.
Trimethylsilyl o-(trimethylsilyl)benzoate (IIa). A
two-necked flask equipped with a dropping funnel and
a reflux condenser with an argon inlet was evacuated,
filled with argon, charged with a solution of 2 g of
o-bromobenzoic acid in 40 ml of diethyl ether, and
cooled to 95 C. After that 9.48 ml of a 2.1 N solu-
tion of butyllithium in hexane was added dropwise
over the course of 40 min. The reaction mixture was
stirred for 1.5 h at 95 C, and a solution of 2.7 ml of
trimethylchlorosilane in 5 ml of diethyl ether was
added dropwise with stirring over the course of
30 min. The mixture was stirred for 20 min at 78 C,
heated to room temperature, and left overnight. The
colorless precipitate was filtered off on a glass filter,
the solvents were removed in a vacuum, and the
residue was distilled to give 1.9 g (72%) of ester IIa,
1
(10 mm Hg). H NMR spectrum (CDCl3), , ppm
(J, Hz): 0.29 s (9H), 0.95 t (3H, 8.0), 1.41 sextet (2H,
8.0), 1.72 quintet (2H, 8.0). 2.96 t (2H, 8.0), 7.61 d
(2H, 8.0), 7.92 d (2H, 8.0).
bp 125 126 C (10 mm Hg). 1H NMR spectrum
(CDCl3), , ppm (J, Hz): 0.35 s (9H), 0.42 s (9H),
7.43 t (1H, JHH 8.0), 7.5 t (1H, JHH 8.0), 7.7 d (1H,
JHH 8.0), 8.05 d (1H, JHH 8.0). Found, %: C 58.11; H
8.12. C13H22O2Si2. Calculated, %: C 58.59; H 8.32.
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